Liver cancer is one of the leading causes of cancer deaths worldwide with fast growing rate in the US in recent years. A patient-friendly early detection and surveillance method would substantially reduce the mortality in this serious disease. 'Liquid biopsy' relying on detection of either circulating tumor cells (CTCs) or extracellular RNAs encapsulated in exosomes in patient blood samples has great potential to achieve this goal. But existing detection methods are far from perfection because CTCs are rare (~5-100 per 1 mL human blood) and exosomes are very small (<100 nm in diameter). Furthermore, none of the existing methods are able to simultaneously capture and detect both circulating exosomes and CTCs. We recently developed a novel and low-cost method 'Tethered Cationic Lipoplex Nanoparticle (TCLN) biochip' that, for the first time, may achieve this goal. In TCLN, molecular beacons (MBs) are pre-loaded in liposome nanoparticles to capture circulating exosomes and detect encapsulated extracellular RNAs from the patient blood or fluid sample without extra complicity. The in situ detection of target RNAs without diluting the sample leads to very high detection sensitivity not achievable by existing methods, e.g. qRT-PCR. The same biochip can also detect intracellular biomarkers in the captured CTCs by lipoplex internalization. Preliminary data in a MYC transgenic mouse model and HCC patient blood samples using miR-21 and miR-181b as biomarkers are very promising. TCLN can be extended to a multiplexing array design to allow the detection of a panel of target RNAs. In this proposal, we plan to evaluate its feasibility for liver cancer early detection and surveillance. Our primary objectives are (1) to compare a panel of target RNAs as biomarkers in tumor tissue and blood samples from MYC transgenic and miR-122 KO mouse models at different disease stages to evaluate the feasibility of using TCLN assay for early cancer detection, and (2) to identify target microRNA/mRNA biomarkers in liver cancer and to conduct a pilot study using blood samples from well-defined liver cancer patient groups to evaluate the relevancy of TCLN assay for cancer use in clinic.